Para-methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity, whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated an HPLC-MS/MS method to measure the compound’s concentrations in plasma, and applied it to describe the pharmacokinetic properties after single dose in rats. In this study we investigated the brain disposition and metabolism of cis-4,4’-DMAR after intraperitoneal injection, and its central behavioral effects. After a single injection of 10 mg/kg, locomotor activity increased, peaking at two hours and disappearing at five hours; in these conditions, brain absorption was very rapid, (tmax 30-60 minutes) and large (brain-to-plasma ratio 24); t1/2 was ~50 min. After 14 daily doses, the compound’s effect on locomotor activity was greater (~20% in comparison with the effect after the first dose), but not for pharmacokinetic reasons. By high resolution mass spectrometry we also identified four metabolites of cis-4,4’-DMAR in plasma and brain of treated rats. Semiquantitive analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in plasma for longer time and at higher concentrations than the parent molecule, and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4’-DMAR, in the conditioning place preference test, suggesting a high risk of addiction in humans.
Brain disposition of cis - para -methyl-4-methylaminorex ( cis -4,4'-DMAR) and its potential metabolites after acute and chronic treatment in rats: correlation with central behavioral effects
MARZO, CLAUDIO MARCELLO;
2017-01-01
Abstract
Para-methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity, whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated an HPLC-MS/MS method to measure the compound’s concentrations in plasma, and applied it to describe the pharmacokinetic properties after single dose in rats. In this study we investigated the brain disposition and metabolism of cis-4,4’-DMAR after intraperitoneal injection, and its central behavioral effects. After a single injection of 10 mg/kg, locomotor activity increased, peaking at two hours and disappearing at five hours; in these conditions, brain absorption was very rapid, (tmax 30-60 minutes) and large (brain-to-plasma ratio 24); t1/2 was ~50 min. After 14 daily doses, the compound’s effect on locomotor activity was greater (~20% in comparison with the effect after the first dose), but not for pharmacokinetic reasons. By high resolution mass spectrometry we also identified four metabolites of cis-4,4’-DMAR in plasma and brain of treated rats. Semiquantitive analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in plasma for longer time and at higher concentrations than the parent molecule, and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4’-DMAR, in the conditioning place preference test, suggesting a high risk of addiction in humans.
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